How it works: Monocytes are isolated from individual patients and treated with a 15 kD granulysin, a molecule that induces the formation of dendritic cells which are injected back into the patient to stimulate the immune system

General Description Granulysin is a cytolytic and proinflammatory molecule expressed by activated human cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. It is expressed as two isoforms: a single mRNA gives rise to a 15 kDa granulysin, a portion of which is cleaved to a 9 kDa protein. The 9 kDa granulysin has been well studied and its characteristics have been well-documented including its cytolytic and proinflammatory properties. Although the 9 kDa protein results from cleavage of the 15 kDa granulysin, the two molecules play very different roles in immune responses. Both recombinant granulysins attract and activate both mouse and human monocyte-derived dendritic cells (DCs) and increase i.p. inflammatory cells in vivo, suggesting they may have utility as an adjuvant in the clinic. In contrast to the 9 kDa protein, the 15 kDa granulysin is not cytolytic. In addition, the 15 kDa protein activates monocytes to differentiate into immature dendritic cells (iDCs) where the 9 kDa protein is unable to achieve this activation. Granulysin has been implicated in several diseases and conditions including infection, cancer, transplantation, autoimmunity, skin and reproductive maladies. Small synthetic forms of granulysin are being developed as novel antibiotics and studies suggest that granulysin may be a useful diagnostic biomarker and/or therapeutic for a wide variety of diseasesScientific Progress The 15 kDa granulysin has been tested in vitro and in vivo. Because mice do not express granulysin, NCI inventors generated mice expressing granulysin as a transgene and demonstrated increased resistance to tumors in this mouse model. In addition, human monocytes were cultured with both isoforms of granulysin to show the cytolytic activity of the 9 kDa isoform and the differentiation of monocytes into iDCs by the 15 kDa protein. The inventors have also shown than 15 kDa granulysin can promote the differentiation of iDCs into mature DCs. This activation and subsequent differentiation induced by 15 kD granulysin may prove important in inducing or regulating immune responses. Consequently, this invention could be used to treat tumors and infections, particularly as an adjuvant for vaccines and immunotherapies. Further, this technology could be used to treat autoimmune disorders and organ transplant rejectionStrengths

Re-injection of self-cells after proliferation and manipulation in culture introduces less regulatory issues than administration of externally created cells

Weaknesses

Should be evaluated in more animal subjects as the animal studies focused on comparing the tumor growth and immune response of an immunotherapy cell model (CT26) in wildtype and granulysin transgenic mice with each group containing 2-6 mice

Patent Status U.S. Patent Application No. 13/501,726 filed 12 April 2012 Google Patent Also filed in Canada, Europe, and Australia Relevant Publications Castiello L, Stroncek DF, Finn MW, Wang E, Marincola FM, Clayberger C, Krensky AM, Sabatino M; J Transl Med2011, 9:41-53. (PMID: 21501511) Clayberger C, Finn MW, Wang T, Saini R, Wilson C, Barr VA, Sabatino M, Castiello L, Stroncek D, Krensky AM. J Immunol2012; 188:6119-6126. (PMID: 22586033) Krensky AM, Clayberger C. Tissue Antigens2009, 73: 193-198. (PMID: 19254247) Tewary P, Yang D, de la Rosa G, Li Y, Finn MW, Krensky AM, Clayberger C, Oppenheim JJ. Blood2010; 116:3465-3474. (PMID: 20660289)Inventor Bio Alan Krensky, M.D. Alan M. Krensky, MD, is Executive for Development for Northwestern Medicine® and Vice Dean for Development and Alumni Affairs at Northwestern University Feinberg School of Medicine. Dr. Krensky attended the University of Pennsylvania for undergraduate and medical school. He went on to Boston Children’s Hospital to serve a residency in pediatrics and a fellowship in nephrology. He also completed a fellowship in immunology at Dana-Farber Cancer Institute. After a year on the Harvard faculty, he moved to Stanford for 23 years where he served as Associate Dean for Children’s Health, Associate Chair for Research (Pediatrics), and the Shelagh Galligan Professor of Pediatrics. During his time at Stanford, Dr. Krensky helped to raise more than $500 million for the Children’s Health Initiative, which he authored and directed. He moved to the National Institutes of Health in 2007, where he served as Deputy Director and was responsible for the Roadmap for Medical Research as director of the Office of Portfolio Analysis and Strategic Initiatives while maintaining a research laboratory in the National Cancer Institute. He joined Northwestern in 2012 to help develop the fundraising campaign for Northwestern Medicine and the Feinberg School of Medicine Dr. Krensky has published more than 280 scientific papers and chapters and holds 12 patents. He has been recognized with research awards from the American Heart Association, American Society of Nephrology, National Kidney Foundation, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, Society for Pediatric Research, American Academy of Pediatrics, March of Dimes, and Burroughs Wellcome. He received a MERIT Award from the National Institutes of Health and is a member of the American Society for Clinical Investigation and Association of American Physicians. He served as president of the Society for Pediatric Research and secretary-treasurer of the American Society for NephrologyCarol Clayberger, Ph.D. Dr. Clayberger is currently a Professor in the Department of Microbiology and Immunology at Northwestern University’s Feinberg School of Medicine. She received her Ph.D. from Yale University and completed her fellowship in Immunology at the Dana Farber Cancer Institute and Harvard University. She was on the faculty at Stanford University and the National Institutes of Health before joining Northwestern in December of 2012. Dr. Clayberger’s laboratory focuses on the immunoregulatory roles of granulysin and the transcription factor KLF13. She has authored more than 150 peer reviewed articles and holds eight issued and one pending patents